This Program Project focuses on strategies for repair of spinal cord injury, assessment of function and development of methods to improve outcome after spinal injury. During the previous funding period we developed cellular and molecular modifications of grafting strategies that will rescue injured neurons and promote regeneration and that are associated with recovery of function. We have also exploited pharmacological interventions that can further enhance function. In addition, we have developed functional analyses of deficits and recovery that provide methods to identify the mechanisms underlying the function that recovers. We build on these findings in the present application with an emphasis on physiological analysis for better assessment of recovery. In one Project we will use fibroblasts modified to express neurotrophic factors to stimulate regeneration of supraspinal axons after acute and chronic spinal hemisections and transections in adult rats. In another Project we will explore the use of genetically modified neural stem cells, a grafting strategy that offers the possibility of replacement of lost neurons, to promote spinal repair, regeneration in adult rats. One Project will continue to identify pharmacological interventions that can act synergistically with the grafts to improve function in animals operated as neonates and as adults. Two Projects are concerned with biomechanical and physiological assessment of function. The goal in one Project is to identify critical interactions between motor cortex and spinal cord that are required for recovery after transections in neonates and adults and to determine whether fetal grafts or grafting strategies developed in two Projects and pharmacological strategies developed in another Project will modify cortical and spinal organization. One Project investigates functional changes in sensorimotor cortex and red nucleus after spinal injury, and after application of transplantation strategies developed in two Projects and pharmacological strategies developed in another Project. Animals in all projects are evaluated in the Behavior Core using a standard set of behavioral measures. This allows direct comparison of functional outcome of grafting strategies. Overall, this Program Project emphasizes the integration of new experimental strategies that promote rescue and regeneration with detailed functional analysis comprised of behavioral, pharmacological, and physiological tests that assess recovery, suggest mechanisms and may ultimately provide neuroprosthetic alternatives.